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1.
Cell ; 185(4): 729-745.e20, 2022 02 17.
Artigo em Inglês | MEDLINE | ID: mdl-35063085

RESUMO

Brain metastasis (BrM) is the most common form of brain cancer, characterized by neurologic disability and an abysmal prognosis. Unfortunately, our understanding of the biology underlying human BrMs remains rudimentary. Here, we present an integrative analysis of >100,000 malignant and non-malignant cells from 15 human parenchymal BrMs, generated by single-cell transcriptomics, mass cytometry, and complemented with mouse model- and in silico approaches. We interrogated the composition of BrM niches, molecularly defined the blood-tumor interface, and revealed stromal immunosuppressive states enriched with infiltrated T cells and macrophages. Specific single-cell interrogation of metastatic tumor cells provides a framework of 8 functional cell programs that coexist or anticorrelate. Collectively, these programs delineate two functional BrM archetypes, one proliferative and the other inflammatory, that are evidently shaped through tumor-immune interactions. Our resource provides a foundation to understand the molecular basis of BrM in patients with tumor cell-intrinsic and host environmental traits.


Assuntos
Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/secundário , Adulto , Idoso , Animais , Biomarcadores Tumorais/metabolismo , Neoplasias Encefálicas/sangue , Neoplasias Encefálicas/imunologia , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Feminino , Variação Genética , Humanos , Evasão da Resposta Imune , Ativação Linfocitária/imunologia , Linfócitos do Interstício Tumoral/imunologia , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Modelos Biológicos , Células Mieloides/patologia , Análise de Componente Principal , RNA-Seq , Análise de Célula Única , Linfócitos T/imunologia
2.
Genes Dev ; 32(19-20): 1267-1284, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30275043

RESUMO

The presence of inflammatory immune cells in human tumors raises a fundamental question in oncology: How do cancer cells avoid the destruction by immune attack? In principle, tumor development can be controlled by cytotoxic innate and adaptive immune cells; however, as the tumor develops from neoplastic tissue to clinically detectable tumors, cancer cells evolve different mechanisms that mimic peripheral immune tolerance in order to avoid tumoricidal attack. Here, we provide an update of recent accomplishments, unifying concepts, and future challenges to study tumor-associated immune cells, with an emphasis on metastatic carcinomas.


Assuntos
Metástase Neoplásica/imunologia , Neoplasias/imunologia , Linfócitos B/imunologia , Carcinoma/imunologia , Carcinoma/secundário , Células Dendríticas/imunologia , Progressão da Doença , Humanos , Vigilância Imunológica , Inflamação/imunologia , Células Matadoras Naturais/imunologia , Macrófagos/imunologia , Neutrófilos/imunologia , Linfócitos T/imunologia
3.
Cancer Immunol Immunother ; 73(5): 93, 2024 Apr 02.
Artigo em Inglês | MEDLINE | ID: mdl-38563861

RESUMO

BACKGROUND: Cartilage oligomeric matrix protein (COMP) is a novel regulator of the tumor microenvironment. Studies in colon cancer and pancreatobiliary adenocarcinoma have revealed COMP expression to be associated with decreased infiltration of immune cells in the tumor microenvironment. Herein, the expression of COMP was investigated in gastric and esophageal adenocarcinoma with particular reference to its the relationship with the immune microenvironment. METHODS: COMP expression was evaluated in tissue microarrays representing primary tumors from 159 patients with chemo- and radiotherapy naïve esophageal and gastric adenocarcinoma and 67 matched samples of lymph node metastases using immunohistochemistry. Additionally, collagen fibers were stained with Sirius Red and evaluated with the FIJI macro TWOMBLI algorithm. RESULTS: The expression of COMP in cancer cells in the entire cohort was associated with shorter overall survival (OS) (p = 0.013) and recurrence-free survival (RFS) (p = 0.029), while COMP expression in the stroma was correlated with shorter RFS (p = 0.042). Similar correlations were found for patients with gastric adenocarcinoma, whereas COMP expression was not prognostic in esophageal adenocarcinoma. Further, in the entire cohort, the expression of COMP in the stroma was correlated with exclusion of different populations of immune cells (CD8+, CD3+, FoxP3+, CD20+) from the tumor microenvironment. Finally, higher density and alignment of collagen fibers were correlated with the expression of COMP in the stroma. CONCLUSIONS: Expression of COMP in gastric and esophageal adenocarcinoma was correlated with shorter OS and RFS. A reduced number of immune cells infiltrated the tumor microenvironment when COMP expression was detected. This phenomenon could be attributed to the denser collagen deposits, a hallmark of tumor fibrosis observed in COMP-expressing tumors.


Assuntos
Adenocarcinoma , Neoplasias Esofágicas , Neoplasias Gástricas , Humanos , Proteína de Matriz Oligomérica de Cartilagem , Prognóstico , Colágeno , Microambiente Tumoral
4.
J Transl Med ; 22(1): 351, 2024 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-38615020

RESUMO

BACKGROUND: Cartilage oligomeric matrix protein (COMP), an extracellular matrix glycoprotein, is vital in preserving cartilage integrity. Further, its overexpression is associated with the aggressiveness of several types of solid cancers. This study investigated COMP's role in ovarian cancer, exploring clinicopathological links and mechanistic insights. METHODS: To study the association of COMP expression in cancer cells and stroma with clinicopathological features of ovarian tumor patients, we analyzed an epithelial ovarian tumor cohort by immunohistochemical analysis. Subsequently, to study the functional mechanisms played by COMP, an in vivo xenograft mouse model and several molecular biology techniques such as transwell migration and invasion assay, tumorsphere formation assay, proximity ligation assay, and RT-qPCR array were performed. RESULTS: Based on immunohistochemical analysis of epithelial ovarian tumor tissues, COMP expression in the stroma, but not in cancer cells, was linked to worse overall survival (OS) of ovarian cancer patients. A xenograft mouse model showed that carcinoma-associated fibroblasts (CAFs) expressing COMP stimulate the growth and metastasis of ovarian tumors through the secretion of COMP. The expression of COMP was upregulated in CAFs stimulated with TGF-ß. Functionally, secreted COMP by CAFs enhanced the migratory capacity of ovarian cancer cells. Mechanistically, COMP activated the Notch3 receptor by enhancing the Notch3-Jagged1 interaction. The dependency of the COMP effect on Notch was confirmed when the migration and tumorsphere formation of COMP-treated ovarian cancer cells were inhibited upon incubation with Notch inhibitors. Moreover, COMP treatment induced epithelial-to-mesenchymal transition and upregulation of active ß-catenin in ovarian cancer cells. CONCLUSION: This study suggests that COMP secretion by CAFs drives ovarian cancer progression through the induction of the Notch pathway and epithelial-to-mesenchymal transition.


Assuntos
Neoplasias Ovarianas , Humanos , Animais , Camundongos , Feminino , Proteína de Matriz Oligomérica de Cartilagem , Receptor Notch3 , Carcinogênese , Transdução de Sinais
5.
Analyst ; 149(21): 5344-5352, 2024 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-39329417

RESUMO

Cancer has become one of the leading causes of death, with approximately ten million people worldwide dying from cancer each year. In most cases, cancer spreads to remote organs and develops a resistance to therapy. To reduce the deadly impact of cancer, novel targets for markers for early detection are necessary. Given the notable influence of rapid chemical turnover on isotope effects, the heightened turnover rate of cholesterol in cancer offers a promising way for investigation. Time-of-Flight Secondary Ion Mass Spectrometry (ToF-SIMS) offers a valuable tool of tracking cholesterol dynamics. Consequently, we employed ToF-SIMS to assess cholesterol alterations, aiming to uncover potential diagnostic vulnerabilities stemming from heightened cholesterol synthesis. Our study explored the chemical profile of cholesterol influenced by cancer cell metabolism using mammary glands from mice, both with and without cancer. Results revealed a significant increase in the fractional abundance of fragment cholesterol peaks (C27H45+) in cancerous tissues, indicating dysregulated cholesterol metabolism within cancer cells. This suggests potential structural weaknesses or incomplete synthesis. Further investigation into carbon isotope incorporation suggests that the isotopic patterns might be due to the integration of heavier carbon isotopes, although these patterns could be affected by other isotopic influences. Nevertheless, understanding isotope effect of cholesterol profiles have the potential to advance our understanding of cancer biology and improve diagnostic approaches.


Assuntos
Colesterol , Espectrometria de Massa de Íon Secundário , Colesterol/análise , Colesterol/metabolismo , Animais , Espectrometria de Massa de Íon Secundário/métodos , Camundongos , Feminino , Isótopos de Carbono/química , Glândulas Mamárias Animais/metabolismo , Glândulas Mamárias Animais/química , Glândulas Mamárias Animais/patologia , Humanos , Neoplasias/metabolismo
6.
Proc Natl Acad Sci U S A ; 116(43): 21704-21714, 2019 10 22.
Artigo em Inglês | MEDLINE | ID: mdl-31591235

RESUMO

Metastatic behavior varies significantly among breast cancers. Mechanisms explaining why the majority of breast cancer patients never develop metastatic outgrowth are largely lacking but could underlie the development of novel immunotherapeutic target molecules. Here we show interplay between nonmetastatic primary breast cancer and innate immune response, acting together to control metastatic progression. The primary tumor systemically recruits IFNγ-producing immune effector monocytes to the lung. IFNγ up-regulates Tmem173/STING in neutrophils and enhances their killing capacity. The immune effector monocytes and tumoricidal neutrophils target disseminated tumor cells in the lungs, preventing metastatic outgrowth. Importantly, our findings could underlie the development of immunotherapeutic target molecules that augment the function of immune effector monocytes and neutrophils.


Assuntos
Citotoxicidade Imunológica/imunologia , Neoplasias Mamárias Animais/patologia , Monócitos/imunologia , Neutrófilos/imunologia , Animais , Linhagem Celular Tumoral , Feminino , Imunidade Inata/imunologia , Imunoterapia/métodos , Interferon gama/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Metástase Neoplásica/imunologia , Metástase Neoplásica/prevenção & controle , Microambiente Tumoral/imunologia
7.
Fetal Pediatr Pathol ; 41(3): 413-425, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33063585

RESUMO

Objective: This study aims to characterize the molecular signatures of sacrococcygeal teratomas (SCTs). Methods: Three SCTs were analyzed with whole genome genotyping. RNA sequencing of 10 SCTs dominated by mature, immature and neuroglial elements was analyzed. Expression in SCT-samples with different elements were compared to each other and to a reference group of malignant pediatric tumors. Macrophages, T- and B-lymphocytes were detected by immunohistochemistry. Results: No chromosomal imbalances were detected. SCTs showed overexpression of genes involved in neurosignaling, DNA-binding molecules and pathways of early germ cells. Genes associated with immune effector processes were overexpressed in mature compared to immature SCTs, and immune cell infiltration was found predominantly around mature epithelial elements. Conclusion: The broad repertoire of histological elements in SCTs reflects differences in transcriptional regulation rather than differences in gene copy numbers. A paucity of immune response in immature SCTs may be a factor contributing to their uninhibited growth.


Assuntos
Região Sacrococcígea , Teratoma , Criança , DNA , Humanos , Imuno-Histoquímica , Região Sacrococcígea/patologia , Teratoma/genética , Teratoma/patologia , Sequenciamento do Exoma
8.
Breast Cancer Res ; 23(1): 27, 2021 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-33602289

RESUMO

BACKGROUND: Patients diagnosed with metastatic breast cancer have poor outcome with a median survival of approximately 2 years. While novel therapeutic options are urgently needed, the great majority of breast cancer research has focused on the primary tumor and less is known about metastatic breast cancer and the prognostic impact of the metastatic tumor microenvironment. Here we investigate the immune landscape in unique clinical material. We explore how the immune landscape changes with metastatic progression and elucidate the prognostic role of immune cells infiltrating primary tumors and corresponding lymph node and more importantly distant metastases. METHODS: Immunohistochemical staining was performed on human breast cancer tissue microarrays from primary tumors (n = 231), lymph node metastases (n = 129), and distant metastases (n = 43). Infiltration levels of T lymphocytes (CD3+), regulatory T lymphocytes (Tregs, FOXP3+), macrophages (CD68+), and neutrophils (NE+) were assessed in primary tumors. T lymphocytes and Tregs were further investigated in lymph node and distant metastases. RESULTS: T lymphocyte and Treg infiltration were the most clinically important immune cell populations in primary tumors. Infiltration of T lymphocytes and Tregs in primary tumors correlated with proliferation (P = 0.007, P = 0.000) and estrogen receptor negativity (P = 0.046, P = 0.026). While both T lymphocyte and Treg infiltration had a negative correlation to luminal A subtype (P = 0.031, P = 0.000), only Treg infiltration correlated to luminal B (P = 0.034) and triple-negative subtype (P = 0.019). In primary tumors, infiltration of T lymphocytes was an independent prognostic factor for recurrence-free survival (HR = 1.77, CI = 1.01-3.13, P = 0.048), while Treg infiltration was an independent prognostic factor for breast cancer-specific survival (HR = 1.72, CI = 1.14-2.59, P = 0.01). Moreover, breast cancer patients with Treg infiltration in their distant metastases had poor post-recurrence survival (P = 0.039). Treg infiltration levels changed with metastatic tumor progression in 50% of the patients, but there was no significant trend toward neither lower nor higher infiltration. CONCLUSION: Treg infiltration could have clinical applicability as a prognostic biomarker, deciphering metastatic breast cancer patients with worse prognosis, and accordingly, could be a suitable immunotherapeutic target for patients with metastatic breast cancer. Importantly, half of the patients had changes in Treg infiltration during the course of metastatic progression emphasizing the need to characterize the metastatic immune landscape.


Assuntos
Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Neoplasias da Mama/terapia , Progressão da Doença , Feminino , Humanos , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Contagem de Linfócitos , Linfócitos do Interstício Tumoral/metabolismo , Linfócitos do Interstício Tumoral/patologia , Pessoa de Meia-Idade , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Modelos de Riscos Proporcionais , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Microambiente Tumoral/imunologia
9.
Exp Cell Res ; 390(1): 111932, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32145253

RESUMO

Patients with estrogen receptor α positive (ERα+) breast cancer can respond to endocrine therapy, but treatment resistance is common and associated with downregulation of ERα expression in the dormant residual cells. Here we show, using long-term NSG xenograft models of human breast cancer and primary human monocytes, in vitro primary cell cultures and tumors from breast cancer patients, that macrophage derived tumor necrosis factor alpha (TNFα) downregulates ERα in breast cancer cells via inactivation of the transcription factor Forkhead box O transcription factor 3a (FOXO3a). Moreover, presence of tumor associated macrophages in the primary tumor of breast cancer patients, was associated with ERα negativity, and with worse prognosis in patients with ERα+ tumors. We propose that pro-inflammatory macrophages, despite being tumoricidal, may have direct effects on tumor progression and endocrine resistance in breast cancer patients. Our findings suggest that TNFα antagonists should be evaluated for treatment of ERα+ breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Receptor alfa de Estrogênio/genética , Proteína Forkhead Box O3/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Animais , Neoplasias da Mama/genética , Células Cultivadas , Regulação para Baixo , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Células MCF-7 , Macrófagos/citologia , Macrófagos/metabolismo , Neoplasias Mamárias Experimentais/genética , Neoplasias Mamárias Experimentais/metabolismo , Camundongos , Células Precursoras de Monócitos e Macrófagos/citologia , Células Precursoras de Monócitos e Macrófagos/metabolismo , Células Precursoras de Monócitos e Macrófagos/transplante
10.
BMC Cancer ; 20(1): 542, 2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32522170

RESUMO

BACKGROUND: Novel biomarkers are required to discern between breast tumors that should be targeted for treatment from those that would never become clinically apparent and/or life threatening for patients. Moreover, therapeutics that specifically target breast cancer (BC) cells with tumor-initiating capacity to prevent recurrence are an unmet need. We investigated the clinical importance of LGR5 in BC and ductal carcinoma in situ (DCIS) to explore LGR5 as a biomarker and a therapeutic target. METHODS: We stained BC (n = 401) and DCIS (n = 119) tissue microarrays with an antibody against LGR5. We examined an LGR5 knockdown ER- cell line that was orthotopically transplanted and used for in vitro colony assays. We also determined the tumor-initiating role of Lgr5 in lineage-tracing experiments. Lastly, we transplanted ER- patient-derived xenografts into mice that were subsequently treated with a LGR5 antibody drug conjugate (anti-LGR5-ADC). RESULTS: LGR5 expression correlated with small tumor size, lower grade, lymph node negativity, and ER-positivity. ER+ patients with LGR5high tumors rarely had recurrence, while high-grade ER- patients with LGR5high expression recurred and died due to BC more often. Intriguingly, all the DCIS patients who later died of BC had LGR5-positive tumors. Colony assays and xenograft experiments substantiated a role for LGR5 in ER- tumor initiation and subsequent growth, which was further validated by lineage-tracing experiments in ER- /triple-negative BC mouse models. Importantly, by utilizing LGR5high patient-derived xenografts, we showed that anti-LGR5-ADC should be considered as a therapeutic for high-grade ER- BC. CONCLUSION: LGR5 has distinct roles in ER- vs. ER+ BC with potential clinical applicability as a biomarker to identify patients in need of therapy and could serve as a therapeutic target for high-grade ER- BC.


Assuntos
Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Carcinoma Intraductal não Infiltrante/química , Receptores Acoplados a Proteínas G/análise , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Biomarcadores Tumorais/imunologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/diagnóstico , Carcinoma Intraductal não Infiltrante/mortalidade , Carcinoma Intraductal não Infiltrante/patologia , Linhagem Celular Tumoral , Feminino , Xenoenxertos , Humanos , Camundongos , Pessoa de Meia-Idade , Prognóstico , RNA Neoplásico/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real , Receptor ErbB-2/análise , Receptores Acoplados a Proteínas G/imunologia , Análise Serial de Tecidos/métodos
11.
Semin Immunol ; 28(2): 197-204, 2016 04.
Artigo em Inglês | MEDLINE | ID: mdl-26976824

RESUMO

Neutrophils have a crucial role in tumor development and metastatic progression. The contribution of neutrophils in tumor development is multifaceted and contradictory. On the one hand, neutrophils prompt tumor inception, promote tumor development by mediating the initial angiogenic switch and facilitate colonization of circulating tumor cells, and on the other hand, have cytotoxic and anti-metastatic capabilities. Our understanding of the role of neutrophils in tumor development has greatly depended on different experimental animal models of cancer. In this review we cover important findings that have been made about neutrophils in experimental animal models of cancer, point to their advantages and limitations, and discuss novel techniques that can be used to expand our knowledge of how neutrophils influence tumor progression.


Assuntos
Modelos Animais de Doenças , Neoplasias/etiologia , Neoplasias/metabolismo , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Neutrófilos/metabolismo , Imunidade Adaptativa , Animais , Progressão da Doença , Humanos , Imunidade Inata , Metástase Neoplásica , Neoplasias/patologia , Neovascularização Patológica/imunologia , Neovascularização Patológica/metabolismo , Neutrófilos/patologia , Microambiente Tumoral/imunologia
12.
Cancer Res Commun ; 2024 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-39400127

RESUMO

The tumor microenvironment of brain metastases has become a focus in the development of immunotherapeutic drugs. However, countless brain metastasis patients have not experienced clinical benefit. Thus, understanding the immune cell composition within brain metastases, and how the immune cells interact with each other and other microenvironmental cell types, may be critical for optimizing immunotherapy. We applied spatial whole transcriptomic profiling with extensive multiregional sampling (19-30 regions per sample) and multiplex immunohistochemistry on formalin-fixed, paraffin-embedded lung cancer brain metastasis samples. We performed deconvolution of gene expression data to infer the abundances of immune cell populations and inferred spatial relationships from the multiplex immunohistochemistry data. We also described cytokine networks between immune and tumor cells and used a protein language model to predict drug-target interactions. Finally, we performed deconvolution of bulk RNA data to assess the prognostic significance of immune-metastatic tumor cellular networks. We show that immune cell infiltration has a negative prognostic role in lung cancer brain metastases. Our in-depth multiomics analyses further reveal recurring intratumoral immune heterogeneity and the segregation of myeloid and lymphoid cells into distinct compartments that may be influenced by distinct cytokine networks. By employing computational modeling, we identify drugs that may target genes expressed in both tumor core and regions bordering immune infiltrates. Finally, we illustrate the potential negative prognostic role of our immune-metastatic tumor cellular networks. Our findings advocate for a paradigm shift from focusing on individual genes or cell types, towards targeting networks of immune and tumor cells.

13.
J Leukoc Biol ; 115(4): 664-678, 2024 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-38060995

RESUMO

The autoimmune regulator (AIRE) is a transcriptional regulator expressed in the thymus and is necessary for maintaining immunological self-tolerance. Extrathymic AIRE expression is rare, and a role for AIRE in tumor-associated innate immune cells has not yet been established. In this study, we show that AIRE is expressed in human pro-tumor neutrophils. In breast cancer, AIRE was primarily located to tumor-associated neutrophils (TANs), and to a lesser extent to tumor-associated macrophages (TAMs) and tumor cells. Expression of AIRE in TAN/TAMs, but not in cancer cells, was associated with an adverse prognosis. We show that the functional role for AIRE in neutrophils and macrophages is to regulate expression of immune mediators and the extrinsic apoptotic pathway involving the Fas/TNFR death receptors and cathepsin G. Here, we propose that the role for AIRE in TAN/TAMs in breast tumors is to regulate cell death and inflammation, thus promoting tumor progression.


Assuntos
Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/patologia , Inflamação/patologia , Macrófagos/metabolismo , Neutrófilos/metabolismo , Macrófagos Associados a Tumor/metabolismo , Macrófagos Associados a Tumor/patologia
14.
Cancer Res Commun ; 4(3): 691-705, 2024 03 07.
Artigo em Inglês | MEDLINE | ID: mdl-38385626

RESUMO

Therapeutic resistance and recurrence remain core challenges in cancer therapy. How therapy resistance arises is currently not fully understood with tumors surviving via multiple alternative routes. Here, we demonstrate that a subset of cancer cells survives therapeutic stress by entering a transient state characterized by whole-genome doubling. At the onset of the polyploidization program, we identified an upregulation of key transcriptional regulators, including the early stress-response protein AP-1 and normoxic stabilization of HIF2α. We found altered chromatin accessibility, ablated expression of retinoblastoma protein (RB1), and enrichment of AP-1 motif accessibility. We demonstrate that AP-1 and HIF2α regulate a therapy resilient and survivor phenotype in cancer cells. Consistent with this, genetic or pharmacologic targeting of AP-1 and HIF2α reduced the number of surviving cells following chemotherapy treatment. The role of AP-1 and HIF2α in stress response by polyploidy suggests a novel avenue for tackling chemotherapy-induced resistance in cancer. SIGNIFICANCE: In response to cisplatin treatment, some surviving cancer cells undergo whole-genome duplications without mitosis, which represents a mechanism of drug resistance. This study presents mechanistic data to implicate AP-1 and HIF2α signaling in the formation of this surviving cell phenotype. The results open a new avenue for targeting drug-resistant cells.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Neoplasias , Humanos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fator de Transcrição AP-1/genética , Regulação para Cima , Transdução de Sinais , Neoplasias/tratamento farmacológico
15.
Front Immunol ; 14: 1167659, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37207219

RESUMO

Introduction: Cartilage Oligomeric Matrix Protein (COMP) is an oncogenic protein that has been associated with a decrease in infiltrating T-cells in periampullary adenocarcinoma. This study aimed to investigate whether this is also the case for colorectal cancer (CRC) and to evaluate the relationship between COMP expression and clinopathological features. Methods: Immunohistochemistry was used to determine the expression levels of COMP in tumor cells and stroma in primary tumors from a cohort of 537 CRC patients. The expression of immune cell markers, including CD3+, CD8+, FoxP3+, CD68+, CD56+, CD163+, and PD-L1, was evaluated previously. Tumor fibrosis was assessed by Sirius Red staining and evaluation of collagen fiber organization. Results: COMP expression correlated positively with TNM-stage and grade of differentiation. Patients with CRC expressing high levels of COMP had significantly shorter OS than those with low COMP expression (p<0.0001), and fewer infiltrating T-cells were detected in tumors with high COMP expression. Additionally, a negative correlation was identified between the expression of COMP and PD-L1 on both tumor cells and immune cells. Cox regression analysis showed that tumors expressing high levels of COMP had significantly shorter OS, independent of all evaluated immune cell markers. Tumor fibrosis was correlated with high expression of COMP in the stroma (p<0.0001), and tumors with high levels of COMP expression and denser fibrosis displayed more sparse immune cell infiltration. Discussion: The results suggest that COMP expression in CRC may exert an immune regulatory effect by increasing dense fibrosis and decreasing immune cell infiltration. These findings support the notion that COMP is an important factor in the development and progression of CRC.


Assuntos
Antígeno B7-H1 , Proteína de Matriz Oligomérica de Cartilagem , Neoplasias Colorretais , Humanos , Antígeno B7-H1/metabolismo , Biomarcadores , Proteína de Matriz Oligomérica de Cartilagem/metabolismo , Prognóstico
16.
Cancers (Basel) ; 15(4)2023 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-36831605

RESUMO

The presence of CD169+ macrophages in the draining lymph nodes of cancer patients is, for unknown reasons, associated with a beneficial prognosis. We here investigated the prognostic impact of tumor-infiltrating CD169+ macrophages in primary tumors (PTs) and their spatial relation to tumor-infiltrating B and T cells. Using two breast cancer patient cohorts, we show that CD169+ macrophages were spatially associated with the presence of B and T cell tertiary lymphoid-like structures (TLLSs) in both PTs and lymph node metastases (LNMs). While co-infiltration of CD169+/TLLS in PTs correlated with a worse prognosis, the opposite was found when present in LNMs. RNA sequencing of breast tumors further confirmed that SIGLEC1 (CD169) expression was associated with mature tertiary lymphoid structure (TLS), and Treg and Breg signatures. We propose that the negative prognostic value related to CD169+ macrophages in PTs is a consequence of an immunosuppressive tumor environment rich in TLSs, Tregs and Bregs.

17.
Front Immunol ; 14: 1180209, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37404831

RESUMO

CD169+ resident macrophages in lymph nodes of breast cancer patients are for unknown reasons associated with a beneficial prognosis. This contrasts CD169+ macrophages present in primary breast tumors (CD169+ TAMs), that correlate with a worse prognosis. We recently showed that these CD169+ TAMs were associated with tertiary lymphoid structures (TLSs) and Tregs in breast cancer. Here, we show that CD169+ TAMs can be monocyte-derived and express a unique mediator profile characterized by type I IFNs, CXCL10, PGE2 and inhibitory co-receptor expression pattern. The CD169+ monocyte-derived macrophages (CD169+ Mo-M) possessed an immunosuppressive function in vitro inhibiting NK, T and B cell proliferation, but enhanced antibody and IL6 secretion in activated B cells. Our findings indicate that CD169+ Mo-M in the primary breast tumor microenvironment are linked to both immunosuppression and TLS functions, with implications for future targeted Mo-M therapy.


Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Macrófagos , Monócitos , Prognóstico , Linfonodos , Microambiente Tumoral
18.
Oncoimmunology ; 12(1): 2184130, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36875552

RESUMO

Despite aggressive treatment, the 5-year event-free survival rate for children with high-risk neuroblastoma is <50%. While most high-risk neuroblastoma patients initially respond to treatment, often with complete clinical remission, many eventually relapse with therapy-resistant tumors. Novel therapeutic alternatives that prevent the recurrence of therapy-resistant tumors are urgently needed. To understand the adaptation of neuroblastoma under therapy, we analyzed the transcriptomic landscape in 46 clinical tumor samples collected before (PRE) or after (POST) treatment from 22 neuroblastoma patients. RNA sequencing revealed that many of the top-upregulated biological processes in POST MYCN amplified (MNA+) tumors compared to PRE MNA+ tumors were immune-related, and there was a significant increase in numerous genes associated with macrophages. The infiltration of macrophages was corroborated by immunohistochemistry and spatial digital protein profiling. Moreover, POST MNA+ tumor cells were more immunogenic compared to PRE MNA+ tumor cells. To find support for the macrophage-induced outgrowth of certain subpopulations of immunogenic tumor cells following treatment, we examined the genetic landscape in multiple clinical PRE and POST tumor samples from nine neuroblastoma patients revealing a significant correlation between an increased amount of copy number aberrations (CNA) and macrophage infiltration in POST MNA+ tumor samples. Using an in vivo neuroblastoma patient-derived xenograft (PDX) chemotherapy model, we further show that inhibition of macrophage recruitment with anti-CSF1R treatment prevents the regrowth of MNA+ tumors following chemotherapy. Taken together, our work supports a therapeutic strategy for fighting the relapse of MNA+ neuroblastoma by targeting the immune microenvironment.


Assuntos
Recidiva Local de Neoplasia , Neuroblastoma , Criança , Animais , Humanos , Proteína Proto-Oncogênica N-Myc , Modelos Animais de Doenças , Macrófagos , Microambiente Tumoral
19.
Cell Rep Med ; 3(6): 100657, 2022 06 21.
Artigo em Inglês | MEDLINE | ID: mdl-35688160

RESUMO

Understanding the complete immune cell composition of human neuroblastoma (NB) is crucial for the development of immunotherapeutics. Here, we perform single-cell RNA sequencing (scRNA-seq) on 19 human NB samples coupled with multiplex immunohistochemistry, survival analysis, and comparison with normal fetal adrenal gland data. We provide a comprehensive immune cell landscape and characterize cell-state changes from normal tissue to NB. Our analysis reveals 27 immune cell subtypes, including distinct subpopulations of myeloid, NK, B, and T cells. Several different cell types demonstrate a survival benefit. In contrast to adult cancers and previous NB studies, we show an increase in inflammatory monocyte cell state when contrasting normal and tumor tissue, while no differences in cytotoxicity and exhaustion score for T cells, nor in Treg activity, are observed. Our receptor-ligand interaction analysis reveals a highly complex interactive network of the NB microenvironment from which we highlight several interactions that we suggest for future therapeutic studies.


Assuntos
Neuroblastoma , Adulto , Humanos , Imuno-Histoquímica , Neuroblastoma/genética , Microambiente Tumoral/genética
20.
Cancers (Basel) ; 13(23)2021 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-34884987

RESUMO

Cartilage oligomeric matrix protein (COMP) is a regulator of the extracellular matrix and is expressed primarily in the cartilage. Recently, COMP expression was also documented in breast cancer patients both in sera and tumor biopsies, in both of which it could serve as an independent prognostic marker. This study aimed to assess COMP as a potential biomarker in the group of metastatic breast cancer patients. Levels of COMP were measured by ELISA in serum samples of 141 metastatic breast cancer patients. Biopsies from primary tumors, synchronous lymph node metastases, and distant metastases were stained for COMP expression. The levels of serum COMP were higher in patients with ER- and HER2-positive tumors when compared to triple-negative tumors and correlated with the presence of bone and lung metastases, circulating tumor cell count, and clusters. Most of the primary tumors expressing COMP (70%) retained the expression also in the lymph node metastases, which correlated with visceral metastases and reduced survival. In conclusion, COMP appears as a valuable biomarker in metastatic breast cancer patients indicating a more severe stage of the disease. Serum COMP levels were associated with specific types of metastases in patients with metastatic breast cancer emphasizing that further studies are warranted to elucidate its potential role as a monitoring marker.

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